Familial benign hypercalcemia (FBH, or hypocalciuric hypercalcemia) is a congenital, lifelong hypercalcemic state occurring in an autosomal dominant pattern of inheritance. Affected individuals also have mild hypermagnesemia and hypophosphatemia, normal to slightly elevated plasma parathyroid hormone (PTH) levels, and usually unremarkable parathyroid glands. Subtotal parathyroidectomy does not mitigate the biochemical abnormalities. The hypercalcemia seems to result primarily from PTH-independent excessive renal tubular reabsorption of calcium, and failure of hypercalcemia to suppress PTH release. While most affected individuals are symptom-free, there are reports of coexisting recurrent pancreatitis, severe neonatal primary hyperparathyroidism, chondrocalcinosis, and other complications in the families. Affected individuals are often misdiagnosed as having mild primary hyperparathyroidism and have unnecessary surgery; regrettably, there is no definitive test for diagnosis of FBH. We have identified 27 families with FBH, including more than 150 affected family members, and are almost ideally suited to carry out a genetic linkage analysis that could ultimately lead to cloning of the gene responsible for FBH. The principal investigator proposes to spend 6 months or more in the laboratories of the internationally-recognized genetics experts Drs. Ray White, Mark Leppert, and Jean-Marc Lalouel, Howard Hughes Medical Institute Laboratories and the Laboratory of Human Genetics, University of Utah, learning the techniques necessary to conduct such a linkage analysis. The White laboratory has demonstrated its ability to go from genetic linkage to cloning of a disease gene, as they have recently accomplished for neurofibromatosis-1. DNA prepared from our 6-10 largest families with FBH will be taken to Utah for the work, so that the sabbatical leave will be directly productive. Techniques to be learned include DNA purification, viral transformation of lymphoblasts, restriction enzyme digestion of DNA, gel electrophoresis and Southern blotting, probing of blots with selected polymorphic markers, and computer analysis of restriction fragment length polymorphisms to achieve linkage of the disease gene with a marker or markers. The work will bring cutting-edge techniques to the applicant's laboratory, complement his ongoing cell biological studies of FBH, allow the logical next step in his NIH-funded studies of FBH, and possibly lead to discovery of a novel calcium regulatory pathway and a specific diagnostic method for FBH. In the future, the techniques will be applicable to the study of other hereditary endocrine diseases by the principal investigator.